About 11,920 new cases of acute myelogenous leukemia (AML; also known as acute myelocytic leukemia, acute myeloid leukemia, acute myeloblastic leukemia, acute granulocytic leukemia or acute nonlymphocytic leukemia) were diagnosed in the United States in 2005 (Surveillance, Epidemiology and End Results [SEER] Program, 2005). The most common acute leukemia affecting adults, AML can occur at any age, but adults age 65 and older are more likely to develop the disease than younger people. In addition, AML accounts for about 15 to 20 percent of childhood acute leukemia cases.
The malignant cell in AML is the myeloblast. In normal hematopoiesis, the myeloblast is an immature precursor of myeloid white blood cells. However, in AML, a single myeloblast accumulates genetic changes which “freeze” the cell in its immature state and prevents differentiation. Such a mutation alone does not cause leukemia; however, when “differentiation arrest” is combined with other mutations which disrupt genes controlling proliferation, the result is the uncontrolled growth of an immature clone of cells (leukemic blasts) which fail to function as normal blood cells and also block production of normal marrow cells. This leads to a deficiency of red cells (anemia), platelets (thrombocytopenia), and normal white cells, especially neutrophils (neutropenia) in the blood, leading to the clinical presentation of AML.
Nearly all patients with AML require treatment as soon after diagnosis as possible. In most patients, intensive chemotherapy (induction therapy), during which at least two different chemotherapeutic agents are administered, is required to achieve remission.
Remission is achieved when blood cell counts gradually approach normal and leukemia cells cannot be identified in blood or marrow. However, in remission, residual leukemic cells are still present but inactive; they do not interfere with normal blood cell development but do have the potential to re-grow and cause a relapse of the leukemia. For this reason, additional chemotherapy with or without autologous stem cell infusion or allogeneic stem cell transplantation usually is advised.
Residual leukemic cells that cannot be detected in the blood or by marrow examination remain in the body during remission. Optimal treatment of AML, therefore, usually requires additional intensive therapy after remission has been achieved (consolidation therapy). Even after the intensive chemotherapy of consolidation therapy, some patients have residual leukemic cells in their marrow (refractory leukemia) and still other patients suffer “relapse” after achieving remission.
One of the greatest difficulties to overcome when treating a patient with AML is that the leukemia cells of some patients are insensitive to chemotherapy drugs. This can lead to a failure of treatment to induce or sustain remission.
There are three known mechanisms of drug resistance in the leukemia cell that protect it from the effects of chemotherapy. First, specific genes encode proteins that evolved to protect the primitive cells from toxins (e.g. P-glycoprotein (multi-drug resistant protein), lung resistance protein, and breast cancer resistance protein). These proteins, and others, may decrease the effectiveness of chemotherapy in acute leukemia cells. Second, chemotherapy takes advantages of apoptosis gene pathways by inducing accentuated and accelerated programmed cell death. In some leukemias, however, these genes are either down-regulated or even blocked, literally blocking cell death as a result of chemotherapy. Third, specific gene families may be active in chemotherapy-resistant cells that result in relapse of the patient's leukemia. To date, no new successful clinical approaches have been found that block one or another of these pathways.
Although the proportion of patients with AML who enter remission, stay in remission for years, or are actually cured, has increased over the past 30 years, AML remains one of the most difficult blood cancers to cure. Because of this difficulty, new therapies for treating AML are essential. There is therefore, a longstanding, urgent need in the art for new methods of treating this devastating disease. The present invention fulfills this need.